The Phlebovirus genus of the Bunyaviridae family is a group of arthropod-borne viruses, having mosquitoes and flies as the usual vectors and a wide variety of animals as primary hosts. Over fifty currently known members defining this group are widely distributed in both hemispheres. The Phlebovirus genus contains a spectrum of important pathogens that can cause fatal disease in humans and domestic animals. Our research plan focuses on creating a vaccine against the Rift Valley fever virus (RVFV). This virus can be transmitted by a wide variety of mosquitoes and spread to distant geographical sites to initiate epizootics. Most recently, RVFV caused a massive epidemic in sub-Saharan Africa in 1997-98 and spread across the Red Sea to Saudi Arabia and Yemen, causing devastating disease outbreaks in sheep and cattle. The RVFV has potential for use in bioterrorism, and its projected effect on U.S. agricultural interests would likely be immense. There is no treatment for humans or vaccine for the livestock that are such important amplifiers of the virus. An experimental vaccine exists for humans, but the number of doses is limited, and there are no prospects for future manufacture. We propose to develop a prototype recombinant vaccine against RVFV infection based on Sindbis virus replicons expressing structural proteins of RVFV. Replicons will be packaged into viral particles composed by structural proteins of Sindbis and other alpha viruses. Immunization by these particles will efficiently protect against RVFV infection, and it will be possible to manufacture this vaccine on an industrial scale. This vaccine will combine the efficiency of live attenuated vaccines and safety of the subunit vaccines. In this proposal we will identify i) the optimal strategy for expression of structural proteins of RVFV by recombinant Sindbis virus, ii) a system for delivery of recombinant genomes into antigen-presenting cells, and iii) the manufacturing procedure for large-scale production of the recombinant viruses. The study will be important for creating a general strategy for development of vaccines against emerging infections, vaccines that require fast design and large-scale production for immediate use. [unreadable] [unreadable]